We and others have found that patients with HbSS who die prematurely have more evidence of renal, hepatic, and cardiopulmonary damage. Our recent work revealed that only 65% of patients with HbSS screened at the NIH Clinical Center were treated with HU despite the vast majority meeting disease criteria severe enough to warrant initiating HU. Because we are a referral center and most patients are managed by their outside hematologist, we have not been able to control what percentage of patients who are followed at outside institutions start HU. Our study also suggests that HU treatment per se is not sufficient to improve survival and decrease organ damage in patients with HbSS. Instead, patients treated with the highest HU doses and who had the highest HbF levels appeared more likely to survive and had less evidence of renal, hepatic, and cardiopulmonary dysfunction over time. Due to the complexity involved in their care, often the focus has not been to push the HU to MTD. Ideally, a dosing algorithm would make the HU dose titration process easier, more effective, and less intimidating for primary providers who frequently manage adult patients with HbSS. Further, a computer program which is able to calculate a HU dose based on patients' blood counts and the timing of most recent HU dose titration would improve the percentage of patients whose HU is increased to MTD. Hydroxyurea dosing in our protocol will be based on a written algorithm which will be derived manually, and by a computer program which was developed at the NIH Clinical Center. Clinical, laboratory, and echocardiographic parameters will be monitored at baseline and after treatment to further study the effect of maximum HbF response on acute complications associated with HbSS and organ function. The protocol was recently approved by the IRB, and we will begin enrolling patients in the near future. A manuscript describing our recent work has been submitted for publication.